Anti-aging effects of chlorpropamide depend on mitochondrial complex-II and the production of mitochondrial reactive oxygen species

• Published in: Acta pharmaceutica Sinica. B Vol. 12; no. 2; pp. 665 - 677
• Main Authors: Mao, Zhifan, Liu, Wenwen, Huang, Yunyuan, Sun, Tianyue, Bao, Keting, Feng, Jiali, Moskalev, Alexey, Hu, Zelan, Li, Jian
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-02-2022; Elsevier
• Subjects: Anti-aging; ATP sensitive potassium channels; Chlorpropamide; Mitochondrial complex II; Mitochondrial reactive oxygen species; Original; Senescence; Succinate dehydrogenase; Sulfonylureas; Senescence; Succinate dehydrogenase; Anti-aging; Sulfonylureas; Chlorpropamide; Mitochondrial reactive oxygen species; ATP sensitive potassium channels; Mitochondrial complex II
• ISSN: 2211-3835; 2211-3843
• DOI: 10.1016/j.apsb.2021.08.007

Sulfonylureas are widely used oral anti-diabetic drugs. However, its long-term usage effects on patients’ lifespan remain controversial, with no reports of influence on animal longevity. Hence, the anti-aging effects of chlorpropamide along with glimepiride, glibenclamide, and tolbutamide were studied with special emphasis on the interaction of chlorpropamide with mitochondrial ATP-sensitive K+ (mitoK-ATP) channels and mitochondrial complex II. Chlorpropamide delayed aging in Caenorhabditis elegans, human lung fibroblast MRC-5 cells and reduced doxorubicin-induced senescence in both MRC-5 cells and mice. In addition, the mitochondrial membrane potential and ATP levels were significantly increased in chlorpropamide-treated worms, which is consistent with the function of its reported targets, mitoK-ATP channels. Increased levels of mitochondrial reactive oxygen species (mtROS) were observed in chlorpropamide-treated worms. Moreover, the lifespan extension by chlorpropamide required complex II and increased mtROS levels, indicating that chlorpropamide acts on complex II directly or indirectly via mitoK-ATP to increase the production of mtROS as a pro-longevity signal. This study provides mechanistic insight into the anti-aging effects of sulfonylureas in C. elegans.
Chlorpropamide delayed aging in Caenorhabditis elegans, MRC-5 cells and doxorubicin-induced aging mice. It acts on complex II directly or indirectly via mitoK-ATP to produce mtROS as a pro-longevity signal. [Display omitted]